PROJECT SUMMARY This proposal describes a five-year training program for the development of a career in clinical research with a scientific focus on understanding the role of obesity in pulmonary arterial hypertension (PAH). This proposal will serve as a vehicle to developing into an independent investigator. To that end, we have established a training plan that includes mentoring, course-work, didactic educational activities, and hands-on research. Steven Kawut, MD, MS, (the primary mentor) is a tenured Professor of Medicine and Epidemiology. He has a track record of successfully mentoring fellows and junior faculty and holds a K24 to support his mentoring activities. An advisory committee has been assembled to guide the candidate's career development. The application focuses on three specific aims. First, in a large prospective cohort of incident patients with PAH, we will examine the impact of obesity measured by body mass index on survival and quality of life outcomes as measured by a general health related quality of life (QOL) questionnaire, the 12-item Medical Outcomes Short Form survey, and a disease-specific QOL questionnaire, the emPHasis-10. The planned analysis will allow for adjustment for potential confounders including disease severity, age, sex, race, ethnicity, socioeconomic status, and insurance coverage. Second, in a retrospective cohort of patients with PAH from the University of Pennsylvania, we will measure thoracic visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) using chest computed tomography and will examine the association of between VAT:SAT ratio and pulmonary hemodynamics and outcomes in this cohort, adjusting for potential confounders including age, sex, race/ethnicity and disease subtype. We will use causal mediation analysis to examine whether progranulin, an adipokine, is a mediator of these associations. Third, we will enroll patients with PAH in a prospective cohort and will obtain serial measurements of body fat using dual-energy X-ray absorptiometry along with serial echocardiograms over the course of one year. We will determine the associations between changes in body fat mass and RV strain over time adjusting for potential confounders including age, sex, disease subtype, disease severity and PAH therapy. Together, these three aims illuminate different phenotypes of obesity and their association with outcomes in PAH. By combining these novel techniques, the applicant hopes to begin to define the different phenotypes of obesity and understand the underlying pathobiologic processes in the hopes of identifying potential novel therapeutic targets to improve survival and quality of life of patients with PAH.